Process for preparing β-lactam compound

ABSTRACT

The present invention provides a process for producing a β-lactam halide compound represented by the general formula (2) which process is characterized in that the hydroxyl group of a β-lactam halide compound represented by the general formula (1) is substituted with a halogen atom or a leaving group. ##STR1##

This application is a 371 of PCT/JP96/00549 filed Mar. 07, 1996.

TECHNICAL FIELD

The present invention relates to a process for preparing β-lactam halidecompounds which are useful as intermediates of antibacterial agentshaving a cephalosporin skeleton with no carbon atom attached to its3-position (JP-A-135859/1983). The invention relates also to a processfor preparing an exo- methylenepenam compound from the β-lactam halidecompound.

The exo-methylenepenam compound of the present invention is an importantintermediate for synthesizing, for example., β-lactamase inhibitor(Bawldwin et al, J. Chem. Soc., Chem. Commun., 1987, 81, S. Torii etal., Antibit. Chem. Lett., 1993, 3, 2253).

BACKGROUND ART

The β-lactam halide compound of the invention represented by the generalformula (2) is prepared by reacting halogen molecules with an allenylβ-lactam compound represented by the general formula (3) as is alreadyknown (Can. J. Chem., 1978, 56, 1335). However, this process affords amixture of α, β- and β, τ-position isomers depending on the kind ofhalogen molecule and is not usable in actuality. This process furthergives the product via an unstable allene compound as an intermediate andtherefore involves many problems on an industrial scale. ##STR2##wherein R¹ and R³ are as defined below, and R⁵ is lower alkyl.

It is also reported that as shown in the diagram, a keto-form β-lactamcompound is enolized into an enol ether or vinyl halide, followed byhalogenation with N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS)in the presence of a radical generating agent (JP-A- 135859/1983). Sincethis process requires use of a hazardous reagent for reaction, processeswhich are industrially more feasible are desired. ##STR3## wherein R⁶ isphthalimido, aryloxyalkaneamido or alkanoyl, R⁷ is thiocyanato,alkanoyl, arylthio, benzothiazolethio, or alkoxycarbonyl which may besubstituted with alkoxyl, cycloalkyl or the like, R⁸ is alkyl which maybe substituted with a halogen, aryl or the like, X is chlorine or thelike, and Y is a halogen atom.

Further a process is already known for preparing the exo-methylenepenamcompound of the invention which is represented by the general formula(5), by the decarboxylation Pummerer-type transition reaction ofpenam-2-carboxylic acid derived from penicillin as illustrated inDiagram (A) (Bawldwin et al., J. Chem. Soc., Chem. Commun., 1987, 81),whereas this process comprises as many as eight reaction steps, and isas low as up to 6% in overall yield and by no means feasible. ##STR4##

Also known are a synthesis process wherein an allenyl β-lactam compoundobtained from penicillin is subjected to acid hydrolysis, followed byintramolecular cyclization (S. Torii et al., Tetrahedron Lett., 1991,32, 7445) as shown in Diagram (B), and a synthesis process wherein anallenyl β-lactam compound is subjected to a reductive cyclizationreaction (S. Torii et al., Synlett., 1992, 878, S. Torii et al.,Chemistry Express, 1992, 7, 885, J. Chem. Soc., Chem. Commun., 1992,1793). These processes nevertheless have various problems such ascumbersomeness of the reaction procedure for industrial operation sincethe reaction is conducted via an unstable allene compound as anintermediate. ##STR5##

An object of the present invention is to provide a process adapted toproduce a β-lactam halide compound represented by the general formula(2) from a β-lactam halide compound represented by the general formula(1) and readily available industrially, in a high yield with a highpurity through a safe and simplified procedure, the process beingdeveloped by realizing milder conditions for effecting halogenation anda reaction for introducing the leaving group.

Another object of the invention is to provide a process adapted toproduce an exo-methylenepenam compound of the general formula (5) fromthe β-lactam halide compound of the general formula (2) in a high yieldwith a high purity through a safe and simplified procedure by developinga novel metal reduction system and a novel electrolytic reduction systemand thereby effecting allenization and conversion to an exo-methylenepenam at the same time efficiently.

DISCLOSURE OF THE INVENTION

The present invention relates to a process for producing a β-lactamhalide compound represented by the general formula (2) which process ischaracterized in that the hydroxyl group of a β-lactam halide compoundrepresented by the general formula (1) is substituted with a halogenatom or a leaving group ##STR6## wherein R¹ is a hydrogen atom, amino orprotected amino, R² is a hydrogen atom, halogen atom, lower alkoxyl,lower acyl, or lower alkyl having hydroxyl or protected hydroxyl as asubstituent, R³ is a hydrogen atom or carboxylic acid protective group,R⁴ is aryl or aryl having a substituent, X is a halogen atom, and n is 0to 2 ##STR7## wherein R¹, R², R³, R⁴, X and n are as defined above, andY is a halogen atom or a leaving group.

The present invention further provides a process for preparing anexo-methylenepenam compound represented by the general formula (5)characterized in that a β-lactam halide compound represented by thegeneral formula (2) is reduced with a metal having a standardoxidation-reduction potential of up to -0.3 (V/SCE) in an amount of atleast one mole per mole of the halide compound and with a metal compoundhaving a higher standard oxidation reduction potential than the metal inan amount of 0.0001 to 10 moles per mole of the halide compound, or issubjected to an electrolytic reduction process to obtain theexo-methylenepenam compound ##STR8## wherein R¹ is a hydrogen atom,amino or protected amino, R² is a hydrogen atom, halogen atom, loweralkoxyl, lower acyl, or lower alkyl having hydroxyl or protectedhydroxyl as a substituent, R³ is a hydrogen atom or carboxylic acidprotective group, R⁴ is aryl or aryl having a substituent, X is ahalogen atom, Y is a halogen atom or a leaving group and n is 0 to 2##STR9## wherein R¹, R² and R³ are as defined above.

Examples of groups mentioned herein are as follows.

Exemplary of the protected amino represented by R¹ are amido groups suchas phenoxyacetamido, p-methylphenoxyacetamido,p-methoxyphenoxyacetamido, p-chlorophenoxyacetamido,p-bromophenoxyacetamido, phenylacetamido, p-methylphenylacetamido,p-methoxyphenylacetamido, p-chlorophenylacetamido,p-bromophenylacetamido, phenylmonochloroacetamido,phenyldichloroacetamido, phenylhydroxyacetamido, thienylacetamido,phenylacetoxyacetamido, α-oxophenylacetamido, benzamido,p-methylbenzamido, p-methoxybenzamido, p-chlorobenzamido,p-bromobenzamido, phenylglycylamido, phenylglycylamido having protectedamino, p-hydroxyphenylglycylamido, p-hydroxyphenylglycylamido havingprotected amino and/or protected hydroxyl, etc.; imido groups such asphthalimido, nitrophthalimido, etc., in addition to the groups disclosedin Theodora W. Greene, 1981, "Protective Groups in Organic Synthesis"(hereinafter referred to merely as the "literature"), Chap. 7 (pp.218˜287). Examples of protective groups for the amino ofphenylglycylamido group and p-hydroxyphenylglycylamido group are thosedisclosed in the literature, Chap. 7 (pp. 218˜287). Examples ofprotective groups for the hydroxyl of p-hydroxyphenylglycylamido groupare those disclosed in the literature, Chap.2 (pp. 10˜72).

Examples of halogen atom represented by R² are fluorine, chlorine,bromine or iodine atom. Exemplary of the lower alkoxyl represented by R²are straight-chain or branched C₁˜4 alkoxyl groups such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy andtert-butoxy groups.

Exemplary of the lower acyl represented by R² are straight-chain orbranched C₁˜4 acyl groups such as formyl, acetyl, propionyl, butyryl andisobutyryl.

Examples of protective groups for the protected hydroxyl in the loweralkyl represented by R² and substituted with hydroxyl or protectedhydroxyl, and for the protected hydroxyl represented by R² are thosedisclosed in the literature, Chap. 2 (pp. 10˜72). The substituted loweralkyl represented by R² may have as its substituent(s) one or at leasttwo same or different groups selected from among hydroxyl and theprotected hydroxyl groups. Such substituent(s) may be positioned on atleast one carbon atom of the alkyl. Examples of lower alkyl arestraight-chain or branched C₁˜4 alkyl group such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

Exemplary of the carboxylic acid protecting group represented by R³ areallyl, benzyl, pmethoxybenzyl, p-nitrobenzyl, diphenylmethyl,trichloromethyl, tert-butyl, and those disclosed in the literature,Chap. 5 (pp. 152˜192).

Examples of aryl and substituted aryl represented by R⁴ are phenyl,naphthyl, nitrogen-containing heterocyclic group, etc. Exemplary of thenitrogen-containing heterocyclic groups are benzothiazol group, triazolgroup, thiazol group, tetrazol group, etc. Exemplary of the substituentwhich may be substituted in the aryl are halogen atoms (such asfluorine, chlorine, bromine, iodine atom), straight-chain or branchedC₁˜4 alkoxyl groups (such as methoxy, ethoxy), straight-chain orbranched C₁˜4 alkylthio groups (such as methythio, ethylthio),straight-chain or branched C₁˜4 alkylsulfonyloxy groups (such asmethanesulfonyloxy, trifluoromethanesulfonyl-oxy), aromatic sulfonyloxyor substituted aromatic sulfonyloxy (such as benzenesulfonyloxy,toluenesulfonyloxy), straight-chain or branched C₁˜4 alkyl groups (suchas methyl, ethyl), amino, amino which has as a substituent one or twostraight-chain or branched C₁˜4 alkyl groups (such as methylamino,dimethylamino, ethylamino, diethylamino), hydroxyl, acyloxy grouprepresented by R'COO-- wherein R' is phenyl, tolyl, or straight-chain orbranched C₁˜4 alkyl group (such as phenylcarbonyloxy, acetyloxy), acylgroup represented by R'CO--wherein R' is as defined above (such asphenylcarbonyl, acetyl), nitro, cyano, phenyl, etc. When the arylrepresented by Ar is phenyl group, the aryl may have 1 to 5, especially1, 2 or 3, same or different groups selected from among the abovesubstituents. When the aryl represented by Ar is naphtyl group, the arylmay have 1 to 7, especially 1, 2 or 3, same or different groups selectedfrom among the above substituents.

Examples of halogen atoms represented by X, Y are fluorine, chlorine,bromine or iodine atom. Exemplary of the leaving groups represented by Yare lower alkylsulfonyloxy or substituted lower alkylsulfonyloxy (suchas methanesulfonyloxy, trifluoromethanesulfonyloxy,trichloromethanesulfonyloxy), aromatic sulfonyloxy or substitutedaromatic sulfonyloxy (such as benzenesulfonyloxy, toluenesulfonyloxy),halogenated sulfonyloxy or substituted halogenated sulfonyloxy (such asfluoromethanesulfonyloxy), lower alkylphosphoryloxy or substituted loweralkylphosphoryloxy (such as trimethylphosphonyloxy,triethylphosphonloxy, tributylphosphoryloxy), aromatic phosphoryloxy orsubstituted aromatic phosphoryloxy (such as triphenylphosphoryloxy,tritolylphosphoryloxy), etc.

The β-lactam compound represented by the general formula (1) for use asa starting material of the present invention can be prepared, forexample, from a β-lactam halide compound represented by the generalformula (4) by a process disclosed in literature (S. Torii et al.,Chemistry Letter, 1990, 1867), or by reacting this compound with ozonein an inert solvent ##STR10## wherein R¹, R², R³, R⁴ and X are asdefined above.

The β-lactam halide compound of the general formula (1) obtained can bepurified in a usual manner for isolation but is usable as prepared forthe next reaction.

A halogenating agent or agent for generating a leaving group is thencaused to act on the hydroxyl group of the β-lactam halide compound ofthe general formula (1) thus obtained, whereby the compound (1) can beconverted to a β-lactam halide compound represented by the generalformula (2). Alternatively, the compound (1) is acted on with theleaving group generating agent first and then with the halogenatingagent, whereby the β-lactam halide compound (2) can be prepared undermilder conditions.

Examples of useful halogenating agents are phosphorus(V ) chlorides suchas phosphorus oxychloride and pentachloride, phosphorus(III ) chloridesand bromides such as phosphorus trichloride and phosphorus tribromide,triarylphosphine-halogen complexes such as triarylphosphine-dichlorinecomplex and triarylphosphine-dibromine complex which may have asubstituent, mixtures of a triarylphosphine or trialkylphosphine whichmay have a substituent and a halogen molecule, thionyl halides such asthionyl chloride and thionyl bromide, sulfonyl halides such as sulfonylchloride and sulfonyl bromide, etc. Usual halogenating agents for thehydroxyl group are usable without any particular limitations. Thesehalogenating agents are used usually in an amount of about 1 to about 50moles, preferably about 1 to about 10 moles, per mole of the compound ofthe general formula (1). The halogenating agent can be used incombination with an inorganic base such as sodium bicarbonate or sodiumcarbonate, organic base such as triethylamine, ethyldiisopropylamine orN,N-dimethylaniline, or basic resin such as Amberlite XE-583. While theabove halogenating agents are usable as the halogenating agent to beused subsequently to the leaving group generating agent used first,other examples of such agents usable for the subsequent reaction includealkali metal halide salts such as lithium chloride and lithium bromide,alkaline-earth metal halide salts such as calcium chloride and calciumbromide, and aluminum halide salts such as aluminum chloride andaluminum bromide. These halogen salts are used usually in an amount ofabout 1 to about 50 moles, preferably about 1 to about 10 moles, permole of the compound of the general formula (1). The halogen salts areusable singly or in combination of at least two of them.

Examples of leaving group generating agents usable are methanesulfonylchloride, trifluoromethanesulfonyl chloride and like lower alkylsulfonylchlorides which may have a substituent, benzenesulfonyl chloride,toluenesulfonyl chloride and like aromatic sulfonic acid chlorides whichmay have a substituent, methanesulfonic anhydride,trifluoromethanesulfonic anhydride and like lower alkylsulfonicanhydrides which may have a substituent, benzenesulfonic anhydride,toluenesulfonic acid anhydride and like aromatic sulfonic anhydrideswhich may have a substituent, diethylphosphoryl chloride and like loweralkylphosphoryl chlorides which may have a substituent,diphenylphosphoryl chloride and like aromatic phosphoryl chlorides whichmay have a substituent, etc. These agents are used usually in an amountof about 1 to about 50 moles, preferably about 1 to about 10 moles, permole of the compound of the general formula (1). The leaving groupgenerating agent can be used in combination with, for example, aninorganic base such as sodium bicarbonate or sodium carbonate, organicbase such as triethylamine, ethyldiisopropylamine orN,N-dimethylaniline, or basic resin such as Amberlite XE-583. Examplesof substituents which may be present in these lower alkylsulfonylchlorides, lower alkylsulfonyl anhydrides and lower alkyl phosphorylchlorides are halogen atoms (such as fluorine, chlorine, bromine andiodine atoms), straight-chain or branched C₁˜4 alkoxyl groups (such asmethoxy, ethoxy), straight-chain or branched C₁˜4 alkylthio groups (suchas methylthio, ethylthio), straight-chain or branched C₁˜4alkylsulfonyloxy groups (such as methanesulfonyloxy,trifluoromethanesulfonyloxy), straight-chain or branched C₁˜4 alkylgroups (such as methyl, ethyl), amino, amino which has as a substituentone or two straight-chain or branched C₁˜4 alkyl groups (such asmethylamino, dimethylamino, ethylamino, diethylamino), acyloxy grouprepresented by R'COO-- wherein R' is phenyl, tolyl, or straight-chain orbranched C₁˜4 alkyl group (such as phenylcarbonyloxy, acetyloxy), acylgroup represented by R'CO-- wherein R' is as defined above (such asphenylcarbonyl, acetyl), nitro, cyano, phenyl, etc. The loweralkylsulfonyl chlorides or anhydrides or lower alkylphosphoryl chloridesmay have 1 to 5, preferably 1 to 3, such substituents which aredifferent or of the same kind. Examples of substituents which may bepresent in the aromatic sulfonyl chlorides, aromatic sulfonyl anhydridesand aromatic phosphoryl chlorides are the same as those exemplified forthe lower alkylksulfonyl chlorides or anhydrides or loweralkylphosphoryl chlorides. In the case where the aromatic group isphenyl, 1 to 5, preferably 1, 2 or 3, such substituents may be present,or when the aromatic group is naphthyl, 1 to 7, preferably 1 to 3, suchsubstituents may be present. These substituents are different or of thesame kind.

Examples of solvents useful in the above reaction are lower alkyl estersof lower carboxylic acids such as methyl formate, ethyl formate, propylformate, butyl formate, methyl acetate, ethyl acetate, propyl acetate,butyl acetate, methyl propionate and ethyl propionate, ketones such asacetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone,methyl isobutyl ketone and diethyl ketone, ethers such as diethyl ether,ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropylether, dibutyl ether, methyl cellosolve and dimethoxyethane, cyclicethers such as tetrahydrofuran, dioxane and dioxolan, nitriles such asacetonitrile, propionitrile, butyronitrile, isobutyronitrile andvaleronitrile, substituted or unsubstituted aromatic hydrocarbons suchas benzene, toluene, xylene, chlorobenzene and anisole, hydrocarbonhalides such as dichloromethane, chloroform, dichloroethane,trichloroethane, dibromoethane, propylene dichloride, carbontetrachloride and Freons, aliphatic hydrocarbons such as pentane,hexane, heptane and octane, cycloalkanes such as cyclopentane,cyclohexane, cycloheptane and cyclooctane, amides such asdimethylformamide and dimethylacetamide, dimethylsulfoxide, etc. Thesesolvents are used singly or in admixture of at least two of them. Thesesolvents are used in an amount of about 10 to about 200 liters,preferably about 20 to about 100 liters, per kilogram of the compound ofthe formula (1). The reaction is conducted usually at -80° C. to 80° C.,preferably -70° C. to 50° C. The reaction can be conducted, as required,in a sealed vessel, or at an atmosphere of an inert gas such as nitrogengas. The resulting halogenated β-lactam compound of the formula (2) canbe isolated by the usual purification method.

The structure of geometric isomer of the α-position substituent islikely to alter during the present reaction or subsequent purificationstep to undergo cis-trans isomerization. This case is to be includedalso within the scope of the invention.

The β-lactam halide compound of the invention represented by the generalformula (2) and prepared by the foregoing process can alternatively beprepared, for example, by the following process. The desired product canbe obtained by reacting a β-lactam compound represented by the generalformula (6) and known in literature (S. Tori et al., Chemistry Lett.,1990, 1867) with sulfonyl anhydride or a sulfonyl halide which may havea substituent and an organic base, or with a phosphorus halide compoundin an inert solvent ##STR11## wherein R¹, R², R³, R⁴ and n are asdefined above.

The reaction is conducted in a suitable solvent. Examples of solventsuseful in the reaction are lower alkyl esters of lower carboxylic acidssuch as methyl formate, ethyl formate, propyl formate, butyl formate,methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methylpropionate and ethyl propionate, ketones such as acetone, methyl ethylketone, methyl propyl ketone, methyl butyl ketone, methyl isobutylketone and diethyl ketone, ethers such as diethyl ether, ethyl propylether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutylether, methyl cellosolve and dimethoxyethane, cyclic ethers such astetrahydrofuran, dioxane and dioxolan, nitriles such as acetonitrile,propionitrile, butyronitrile, isobutyronitrile and valeronitrile,substituted or unsubstituted aromatic hydrocarbons such as benzene,toluene, xylene, chlorobenzene and anisole, hydrocarbon halides such asdichloromethane, chloroform, dichloroethane, trichloroethane,dibromoethane, propylene dichloride, carbon tetrachloride and Freons,aliphatic hydrocarbons such as pentane, hexane, heptane and octane,cycloalkanes such as cyclopentane, cyclohexane, cycloheptane andcyclooctane, amides such as dimethylformamide and dimethylacetamide,cyclic amides such as N-methylpyrrolidinone, dimethylsulfoxide, etc.These solvents are used singly or in admixture of at least two of them.These solvents may contain water as required. These solvents are used inan amount of about 10 to about 200 liters, preferably about 20 to about100 liters, per kilogram of the compound of the formula (6). Thereaction is conducted usually at -78° C. to 60° C., preferably -40° C.to 30° C. Examples of useful bases are N,N,N-tri lower alkyl amines suchas trimethylamine, dimethylethylamine, triethylamine anddiisopropylethylamine, N-lower alkyl azacycloalkanes such asN-methylpiperidine and N-ethylpiperidine, N-lower alkylazaoxycycloalkanes such as N-methylmorpholine and N-ethylmorpholine,N-phenyl lower alkyl-N,N-di lower alkyl amines such asN-benzyl-N,N-dimethylamine and N-benzyl-N,N-diethylamine, N,N-dialkylaromatic amines such as N,N-dimethylaniline, nitrogen-containingaromatic amines such as pyridine, bicycloamines such asdiazabicycloundecene and diazabicyclononene, and a mixture of theseamines. These bases are used usually in an amount of 1 to 10 equivalentsbased on the β-lactam compound of the formula (6). When required, it isrecommended the base is added until the β-lactam compound of the formula(6) is consumed. The resulting halogenated β-lactam compound of theformula (2) can be isolated by the usual purification method but can beused in the next reaction without purification.

The β-lactam halide compound represented by the general formula (2) canbe converted to an exo- methylenepenam compound represented by thegeneral formula (5) by reacting the halogen atom of the compound (2)with a metal having a standard oxidation-reduction potential of up to-0.3 (V/SCE) in an amount of at least one mole per mole of the compound(2) and a metal compound having a higher standard oxidation-reductionpotential than the metal in an amount of 0.0001 to 10 moles per mole ofthe compound (2), or by subjecting the compound (2) to an electrolyticreduction process in an organic solvent. It is thought that the abovereaction of the invention first forms an allene intermediate as shownbelow, followed by the reduction of the group S--SOnR⁴ to give anexo-methylenepenam derivative. ##STR12##

Examples of metals having a standard oxidation-reduction potential of upto -0.3 (V/SC) are magnesium, aluminum, zinc, iron, nickel, tin, lead,etc., among which magnesium, aluminum, zinc and tin are desirable touse. The shape of these metals is not limited particularly but can beany of a wide variety of forms such as powder, plate, foil, lump andwire. Preferably, the metal to be used is in the form of a powder orfoil. The particle size of the powdery metal is preferably about 100 toabout 300 mesh although variable over a wide range. These metals areused usually in an amount of about 1 to about 50 moles, preferably about1 to about 10 moles, per mole of the compound of the general formula(2).

Examples of metal compounds having a higher standard oxidation-reductionpotential than the above metals are lead compounds (such as leadfluoride, lead chloride, lead bromide, lead iodide and like leadhalides, lead nitrate, lead sulfate, lead perchlorate, lead borate, leadcarbonate, lead phosphate and like inorganic salts of lead, leadacetate, lead oxalate, lead stearate and like fatty acid salts of lead,lead oxide and lead hydroxide), copper compounds (such as copperfluoride, copper chloride, copper bromide, copper iodide and like copperhalides, copper nitrate, copper sulfate, copper perchlorate, copperborate, copper carbonate, copper phosphate and like inorganic salts ofcopper, and copper oxalate), titanium compounds (such as titaniumfluoride, titanium chloride, titanium bromide, titanium iodide and liketitanium halides, and titanium nitrate, titanium sulfate and likeinorganic salts of titanium), bismuth compounds (such as bismuthfluoride, bismuth chloride, bismuth bromide, bismuth iodide and likebismuth halide, bismuth nitrate, bismuth sulfate and like inorganicsalts of bismuth), antimony compounds (such as antimony fluoride,antimony chloride, antimony bromide, antimony iodide and like antimonyhalides, antimony sulfate and like inorganic salts of antimony, andantimony oxide), and nickel compounds (such as nickel fluoride, nickelchloride, nickel bromide, nickel iodide and like nickel halides, nickelnitrate, nickel sulfate, nickel perchlorate, nickel borate, nickelcarbonate, nickel phosphate and like inorganic salts of nickel, nickelacetate and like fatty acid salts of nickel, tetrachloronickel(II)tetraethylammonium, tetrabromonickel(II) tetraethylammonium,hexamminenickel(II), tris(ethylenediamine)nickel(II) sulfate,ethylenediaminetetraaquanickel(II) sulfate monohydrate,dinitrobis(ethylenediamine)nickel(II) perchlorate, bisperchlorate(N,N-dimethylethylenediamine)nickel(II) perchlorate and likeinorganic complexes of nickel, dichloro(bipyridyl)nickel(II),chloro(n-cyclopentadienyl)(triphenylphosphine)nickel(II),dibromobis(triphenylphosphine)nickel(II),dichlorobis{1,1'-(diphenylphosphino)ferrocene}nickel(II) and likeorganic complexes of nickel(II), andtetrakis(triphenylphosphine)-nickel(0),tris(triphenylphosphine)nickel(0), nickel(0)acetylacetonato, nickel(0)hexafluoroacetylacetonato and like organic complexes of nickel(0)).These metal compounds may be used singly or as a mixture of at least twoof them. These metal compounds are used usually in an amount of 0.0001to 30 moles, preferably 0.001 to 10 moles, per mole of the compound ofthe general formula (2).

Examples of combinations of metals up to -0.3 (V/SCE) in standardoxidation-reduction potential and metal compounds having a higherstandard oxidation-reduction potential are Al/Pb compound, Al/Bicompound, Zn/Pb compound, Zn/Bi compound, Mg/Bi compound, Mg/Cucompound, Sn/Ti compound, Sn/Bi compound, Sn/Sb compound, etc., amongwhich the combinations of Al/Pb compound and Zn/Bi compound arepreferred.

Examples of useful solvents for the present reaction are the same asthose for use in the reaction for preparing the compound of the generalformula (2) from the compound of the general formula (6). These solventsare usable also as rendered hydrous. These solvents are used usually inan amount of about 10 to about 200 liters, preferably about 20 to about100 liters, per kg of the compound of the general formula (2). Thereaction is conducted at a temperature usually of -10 to 80° C.,preferably of 0 to 50° C. The reaction of the invention proceedssatisfactorily even around room temperature. Further when required, thereaction can be conducted within a closed container or in an insertsolvent such as nitrogen gas. The exo- methylenepenam derivative of theformula (5) obtained can be isolated by a usual purification procedure.

According to the present invention, the desired exo-methylenepenamderivative of the general formula (5) can be prepared also byelectrolytically reducing the compound (2) in an organic solvent. Theorganic solvent for use in the electroreduction reaction of theinvention can be any of the solvents useful for the foregoing reductionreaction. In carrying out the electroreduction reaction of the presentinvention, a supporting electrolyte is added to the reaction system.Examples of useful supporting electrolytes are metal perchlorate saltssuch as lithium perchlorate, sodium perchlorate and magnesiumperchlorate, ammonium perchlorate salts such as ammonium perchlorate,tetraethylammonium perchlorate and tetrabutylammonium perchlorate,ammonium halide salts such as ammonium chloride, ammonium bromide,ammonium iodide, tetraethylammonium chloride and tetrabutylammoniumbromide, metal tetraflurobate salts such as lithium tetrafluroborate andsodium tetraflurobate, ammonium tetrafluroborate salts such astetraethylammonium tetrafluroborate and tetrabutylammoniumtetrafluroborate, amines such as triethylamine, collidine, lutidine,pyridine, piperidine, N-methylmorpholine, 1,5- diazabicyclo3,4,0!nonene-5 (DBN) and 1,5-diazabicyclo 5,4,0!undecene-5 (DBU),carboxylic acids such as acetic acid, monochloroacetic acid andtrifluoroacetic acid, etc. These support electrolytes are used singly orin the form of a mixture of at least two of them. Preferable to use arethe carboxylic acids. The support electrolyte is used usually in anamount of about 0.1 to about 100 wt. % , preferably about 0.1 to about50 wt. % , based on the solvent.

A wide variety of electrodes useful for usual electrolytic reactions areusable for the electrolytic reduction process of the present invention.For example, platinum, tin, aluminum, stainless steel, nickel, leadoxide, carbon, iron oxide, titanium, etc. are usable as materials forthe positive electrode, and platinum, tin, aluminum, stainless steel,zinc, lead, copper, carbon, etc. as materials for the negativeelectrode. It is preferable to use tin, zinc, lead and copper for thenegative electrode.

It is likely that the electroreduction of the invention will be effectedwith an improved current efficiency by adding to the electrolytic systema metal halide, inorganic acid salt, organic acid salt or oxide havingan oxidation reduction potential not higher than that of the negativeelectrode material used. Examples of such additives usable are halidesof metals such as tin, zinc, lead, bismuth and titanium (e.g.,fluorides, chlorides, bromides and iodides), inorganic acid salts (suchas nitrates, sulfates, perchlorates, borates, phosphates andcarbonates), organic acid salts (such as oxalates, stearates andacetates), oxides, etc. These additives can be used singly or in theform of a mixture of at least two of them. Such additives are used in anamount of about 0.1 to about 1 mole per mole of the compound of thegeneral formula (2). If the additive is used, the supporting electrolyteneed not always be used as the case may be.

The electroreduction of the present invention is characterized in thatthis process can be practiced within a single cell without a need toseparate the positive electrode from the negative electrode although theelectrodes can be separated by a partition membrane. The reactiontemperature is usually in the range of -10° C. to 50° C.

The present reaction can be carried out either at a constant current orat a constant voltage. However, it is desirable to use theconstant-current electrolysis process in view of the simplicity of thedevice and procedure. While the electrolysis can be effected with directcurrent or alternating current, it is also possible to conduct thereaction by changing the direction of current every second or every 30seconds. The current density is usually 1 to 500 mA/cm², preferably 1 to50 mA/cm². The quantity of electricity to be used is usually 2 to 10F/mole, preferably 2 to 5 F/mole although the quantity varies with theshape of the electrolytic cell, the kind of compound (2) and the kind ofsolvent used and can not therefore be determined specifically. Thereaction is completed by passing the above-mentioned quantity ofelectricity.

The exo-methylenepenam derivative of the formula (5) obtained can beisolated by a usual purification procedure.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention will be described below in detail with referenceto examples, wherein Ph stands for C₆ H₅ --, Et for ethyl, Bu for butyland bby for bipyridyl.

EXAMPLE 1

A 100 mg quantity of compound (1a) (R¹ =PhCH₂ CONH, R² =H, R³ =CH₂ C₆ H₄OCH₃ -p, R⁴ =Ph, X=Cl) was weighed out, placed into a 10-ml egg-planttype flask and dissolved in 11 18 Nl of N,N-dimethylformamide. To thesolution was added a solution of 18 Nl of phosphorus oxychloride in 1 mlof N,N-dimethylformamide, followed by stirring at room temperature for 1hour. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with water twice and then withbrine once and thereafter dried over anhydrous sodium sulfate. Theresulting extract was concentrated in vacuo to remove the solvent, andthe residue was subsequently purified by silica gel columnchromatography to afford compound 2a (Y=Cl) (95 mg, 92%). ¹ H--NMR(CDCl₃)δ:3.64(d, J=16.8 Hz, 1H), 3.71(d, J=16.8 Hz, 1H), 3.81(s, 3H),4.27(d, J=12.2 Hz, 1H), 4.70(d, J=12.2 Hz, 1H), 4.73(dd, J=5.6, 6.4 Hz,1H), 5.09(d, J=11.8 Hz, 1H), 5.20(d, J=11.8 Hz, 1H), 5.87(d, J=5.6 Hz,1H), 5.97(d, J=6.4 Hz, 1H), 6.87˜7.74(m, 14H).

EXAMPLES 2 to 7

The same reaction as in Example 1 was performed using the followinghalogenating agents.

    ______________________________________    Example      halogenating agent                              yield (%)    ______________________________________    2            (COCl).sub.2 90    3            SOCl.sub.2   86    4            PCl.sub.3    89    5            PCl.sub.5    83    6            S.sub.2 Cl.sub.2                              78    7            Vilsmeyer    91                 reagent    ______________________________________

EXAMPLES 8 to 15

The same reaction as in Example 1 was performed using Vilsmeyer reagentand the following solvents.

    ______________________________________    Example       solvent    yield (%)    ______________________________________    8             CH.sub.2 Cl.sub.2                             85    9             CH.sub.2 ClCH.sub.2 Cl                             80    10            CHCl.sub.3 81    11            THF        78    12            dioxane    82    13            dioxolan   85    14            DME        76    15            NMP        89    ______________________________________

EXAMPLE 16

A 200 mg quantity of compound (1a) (R¹ =PhCH₂ CONH, R² =H, R₃ =CH₂ C₆ H₄OCH₃ -p, R₄ =Ph, X=Cl), 73 mg of tosyl chloride and 81 mg of sodiumcarbonate were weighed out, placed into 10-ml egg-plant type flask andstirred at 3° C. for 2 hours along with 2 ml of N,N-dimethylformamide.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with water twice and then with brineonce, and thereafter dried over anhydrous sodium sulfate. The resultingextract was concentrated in vacuo to remove the solvent, and the residuewas subsequently purified by silica gel column chromatography, givingcompound 2b (Y=OSO₂ C₆ H₄ --CH₃ -p) (236 mg, 95% ). ¹H--NMR(CDCl₃)δ:2.38(s, 3H), 3.62(s, 2H), 3.90(s, 3H), 4.51(d, J=13.8 Hz,1H), 4.82(d, J=13.8Hz, 1H), 5.27(s, 2H), 5.47(dd, J=4.7, 9.2 Hz, 1H),5.91(d, J=4.7 Hz, 1H), 6.28(d, J=9.2 Hz, 1H), 6.96˜7.91(m, 18H).

EXAMPLES 17 to 21

The same reaction as in Example 16 was preformed using the followingsolvents.

    ______________________________________    Example        solvent  yield (%)    ______________________________________    17             NMP      93    18             THF      86    19             dioxane  85    20             dioxolan 85    21             CH.sub.2 Cl.sub.2                            72    ______________________________________

EXAMPLE 22

A 200 mg quantity of compound (1a) (R¹ =PhCH₂ CONH, R² =H, R³ =CH₂ C₆ H₄OCH₃ -p, R⁴ =Ph, X=Cl) was weight out, placed into a 10-ml egg-planttype flask and cooled to -78° C. with addition of 2 ml of methylenechloride. To the cooled mixture were added 64 ml oftrifluoromethanesulfonic acid anhydride and 106 ml of triethylamine,followed by stirring at the same temperature for 20 minutes. Thereaction mixture was poured into 1N hydrochloric acid and extracted withmethylene chloride. The extract was washed with water twice and thenwith brine once, and thereafter dried over anhydrous sodium sulfate. Theresulting extract was concentrated in vacuo to remove the solvent, andthe residue was purified by silica gel column chromatography, givingcompound 2c (Y=OSO₂ CF₃) (223 mg, 92%). ¹ H--NMR (CDCl₃)δ:3.62(d, J=19.2Hz, 1H), 3.69 (d, J=19.2 Hz, 1H) , 3.79 (s, 3H), 4.31 (d, J=14.4 Hz,1H), 4.74 (d, J=14.4 Hz, 1H), 4.83(dd, J=5.4, 6.9 Hz, 1H), 5.15(d,J=11.7 Hz, 1H), 5.23(d, J=11.7 Hz, 1H), 5.95(d, J=6.9 Hz, 1H), 6.00(d,J=5.4 Hz, 1H) , 6.88˜7.78 (m, 14H)

EXAMPLE 23

Five gram of compound (2c) (R¹ =PhCH₂ CONH, R² =H, R³ =CH₂ C₆ H₄ OCH₃-p, R⁴ =Ph, X=Cl, Y=OSO₂ CF₃) obtained in Example 22, 2.5 g of aluminumchloride and 2.8 g of lithium chloride were weighed out, placed into a200-ml egg- plant type flask and stirred at room temperature for 4 hoursand 20 minutes with addition of 125 ml of N- methylpyrrolidone. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with water twice and then with brine once, andthereafter dried over anhydrous sodium sulfate. The resulting extractwas concentrated in vacuo to remove the solvent, and the residue waspurified by silica gel column chromatography, affording compound 2a(Y=Cl) (3.87 g, 91%). The resulting compound was fully identical withthat of Example 1 in ¹ H NMR.

Reference Example 1

A 100 mg quantity of compound (2a) of the invention was weighed out anddissolved in 2 ml of NMP. To the solution were added 300 mg of aluminumchloride and 100 mg of zinc, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was poured into 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasconcentrated in vacuo, followed by silica gel column chromatography forpurification, giving 3-chlorocephem (4). The compound 3-chlorocephem (4)can be converted by a process disclosed in literature to cefaclor whichis widely used as an oral preparation. Stated more specifically, thecompound (4) is deprotected at the 7- position with phosphoruspentachloride and pyridine (JP-A-3356/1986) and thereby converted to acompound (5), into which an amido side chain is introduced at the7-position. Subsequently, the ester group at the 4-position isdeprotected, giving cefaclor (JP-A-39313/1986). Given below is thereaction formula. ##STR13##

EXAMPLE 24

A 100 mg quantity of compound (2a) (R¹ =PhCH₂ CONH, R² =H, R³ =CH₂ C₆ H₄OCH₃ -p, R⁴ =Ph, X=Cl, Y=Cl), 100 mg of lead bromide and 100 mg ofaluminum powder were weighed out, placed into a 10-ml egg-plant typeflask and stirred at room temperature for 1 hour with addition of 2 mlof N,N-dimethylformamide. The reaction mixture was poured into 1Nhydrochloric acid and extracted with ethyl acetate. The extract waswashed with water twice and then with brine once, and thereafter driedover anhydrous sodium sulfate. The resulting extract was concentrated invacuo to remove the solvent, and the residue was purified by silica gelcolumn chromatography, giving compound 5a (67 mg, 99% ).

¹ H--NMR (CDCl₃)δ: 3.61(s, 2H), 5.25(m, 2H), 5.35(m, 1H), 5.59(d, J=4.0Hz, 1H), 5.75(dd, J=4.0, 8.9 Hz, 1H), 6.12(d, J=8.9 Hz, 1H), 6.84(s,1H), 7.22˜7.40(m, 15H)

EXAMPLE 25

The same reaction as in Example 24 was conducted using,. as a startingmaterial, compound (2d) (R¹ =PhCH₂ CONH, R² =H, R³ =CHPh₂, R⁴ =Ph, X=Cl,Y=Cl) to obtain the compound 5b (68 mg, 97% ).

¹ H--NMR (CDCl₃)δ: 3.61(s, 2H), 3.80(s, 3H), 5.11(s, 2H), 5.18(dd,J=1.5, 1.7 Hz, 1H), 5.24(dd, J=1.5, 2.2 Hz, 1H), 5.35(dd, J=1.7, 2.2 Hz,1H), 5.57(d, J=4.0 Hz, 1H), 5.75(dd, J=4.0, 9.3 Hz, 1H), 6.07(d, J=9.3Hz, 1H), 6.85˜7.40(m, 9H)

EXAMPLE 26

The same reaction as in Example 24 was conducted using, as a startingmaterial, Compound (2e) (R¹ =PhCH₂ CONH, R² =H, R³ =CH₃, R⁴ =Ph, X=Cl,Y=Cl) to obtain the compound 5c (60 mg, 98% )

¹ H--NMR (CDCl₃)δ: 3.63(ABq,J=2.7 Hz, 2H), 3.78(s, 3H), 5.19(dd, J=1.9,1.9 Hz, 1H), 5.28(dd, J=1.9, 1.9 Hz, 1H), 5.40(dd, J=1.9, 1.9 Hz, 1H),5.60(d, J=4.0 Hz, 1H), 5.77(dd, J=4.0, 8.8 Hz, 1H), 6.20(d, J=8.8 Hz,1H), 7.27˜7.37(m, 5H)

EXAMPLE 27

The same reaction as in Example 24 was conducted using, as a startingmaterial, Compound (2f) (R¹ =H, R² =H, R³ =CH₂ C₆ H₄ OCH₃ -p, R⁴ =Ph,X=Cl, Y=Cl) to obtain the compound 5d (54 mg, 90% ).

¹ H--NMR (CDCl₃)δ: 3.16(dd, J=1.5, 16.0 Hz, 2H), 3.66(dd, J=4.0, 16.0Hz, 1H), 3.82(s, 3H), 5.13(s, 2H), 5.24(dd, J=1.8, 1.8 Hz, 1H), 5.28(dd,J=1.8, 1.8 Hz, 1H), 5.32(dd, J=1.8, 1.8 Hz, 1H), 5.38(dd, J=1.5, 4.0 Hz,1H), 6.87˜7.30(m, 4H)

EXAMPLE 28

The same reaction as in Example 24 was conducted using, as a startingmaterial, Compound (2g) (R¹ =H, R² =H, R³ =CHPh₂, R⁴ =Ph, X=Cl, Y=Cl) toobtain the compound 5e (55 mg, 87% ). ¹ H--NMR (CDCl₃)δ: 3.12(dd, J=1.5,16.0 Hz, 2H), 3.60(dd, J=4.1, 16.0 Hz, 1H), 5.23(dd, J=1.8,1.8 Hz, 1H),5.32(dd, J=1.8, 1.8 Hz, 1H), 5.36(dd, J=1.5, 4.1 Hz, 1H), 5.37(dd,J=1.8, 1.8 Hz, 1H), 6.87(s, 1H), 7.27˜7.35(m, 10H).

EXAMPLE 29

The same reaction as in Example 24 was conducted using, as a startingmaterial, Compound (2h) (R¹ =PhCH₂ CONH, R² =H, R³ =CH₂ C₆ H₄ OCH₃ -p,R⁴ =Ph, X=Cl, Y=OSO₂ CF₃) to obtain the compound 5a (49 mg, 86% ). Theresulting compound was fully identical with that of Example 24 inspectral data.

EXAMPLE 30

The same reaction as in Example 24 was conducted using, as a startingmaterial, Compound (2i) (R¹ =PhCH₂ CONH, R² =H, R³ =CHPh₂, R⁴ =Ph, X=Cl,Y=OSO₂ CF₃) to obtain the compound 5b (51 mg, 85% ). The resultingcompound was fully identical with that of Example 25 in spectral data.

EXAMPLE 31

The same reaction as in Example 24 was conducted using, as a startingmaterial, Compound (2j) (R¹ =PhCH₂ CONH, R² =H, R³ =CH₂ C₆ H₄ OCH₃ -p,R⁴ =Ph, X=Cl, Y=OSO₂ C₆ H₄ CH₃ -p) to obtain the compound 5a (50 mg, 76%). The resulting compound was fully identical with that of Example 24 inspectral data.

EXAMPLE 32

The same reaction as in Example 24 was conducted using, as a startingmaterial, Compound (2k) (R¹ =PhCH₂ CONH, R² =H,. R³ =CHPh₂, R⁴ =Ph,X=Cl, Y=OSO₂ C₆ H₄ CH₃ -p) to obtain the compound 5b (52 mg, 72% ). Theresulting compound was fully identical with that of Example 25 inspectral data.

EXAMPLES 33 to 41

The same reaction as in Example 24 was performed using the followingreducing agents.

    ______________________________________    Example  metal compound                         amount     metal                                         yield (%)    ______________________________________    33       PbBr.sub.2  0.1 eq.    Al   92    34       PbBr.sub.2  1 eq.      Zn   75    35       PbCl.sub.2  1 eq.      Al   80    36       Pb(OAc).sub.2                         1 eq.      Al   70    37       BiCl.sub.3  1 eq.      Al   72    38       BiCl.sub.3  1 eq.      Zn   83    39       BiCl.sub.3  1 eq.      Sn   72    40       AlCl.sub.3  1 eq.      Zn   85    41       AlCl.sub.3  1 eq.      Mg   71    ______________________________________

EXAMPLES 42 to 47

The same reaction as in Example 24 was preformed using the followingsolvents.

    ______________________________________    Example       solvent     yield (%)    ______________________________________    42            NMP         98    43            DMA         93    44            HMPA        82    45            DMF/CH.sub.2 Cl.sub.2                              79    46            DMF/CF.sub.3 COOH                              98    47            NMP/CF.sub.2 COOH                              95    ______________________________________

EXAMPLE 48

A 100 mg quantity of compound (2a) (R¹ =PhCH₂ CONH, R² =H, R³ =CH₂ C₆ H₄OCH₃ -p, R⁴ =Ph, X=Cl, Y=Cl), 11 mg of lead bromide and 50 mg oftetraethylammonium tosylate were weighed out, placed into a 20-mlbranched test tube and stirred with addition of 10 ml ofN,N-dimethylformamide to prepare a solution. Electricity was passedthrough the solution in an amount of 5 F/mole with a current of 7.5 mA(5 mA/cm²) via a positive electrode of aluminum and a negative electrodeof platinum provided in the solution. The reaction mixture was pouredinto 1N hydrochloric acid and extracted with ethyl acetate. The extractwas washed with water twice and then with brine once, and thereafterdried over anhydrous sodium sulfate. The resulting extract wasconcentrated in vacuo to remove the solvent, and the residue wassubsequently purified by silica gel column chromatography, givingcompound 5a (54 mg, 80%).

EXAMPLES 49 to 59

The same reaction was performed using the following electrodes and thesame other reaction conditions as above.

    ______________________________________    Example   cathode      anode  yield (%)    ______________________________________    49        Al           C      70    50        Al           Al     75    51        Al           Pb     72    52        Al           Zn     78    53        Al           Sn     76    54        Sn           Pt     69    55        Sn           Pb     74    56        Sn           Sn     72    57        Zn           Pb     75    58        Zn           Zn     70    59        Pb           Pb     76    ______________________________________

EXAMPLES 60 to 67

The same reaction was performed using the following supportingelectrolyte and the same other reaction conditions as above.

    ______________________________________    Example       electrolyte                            yield (%)    ______________________________________    60            Et.sub.4 NBr                            65    61            Et.sub.4 NClO.sub.4                            73    62            Bu.sub.4 NBr                            62    63            LiClO.sub.4                            68    64            H.sub.2 SO.sub.4                            70    65            CH.sub.3 COOH                            73    66            CH.sub.3 COOH                            70    67            Bu.sub.4 NBF.sub.6                            62    ______________________________________

EXAMPLES 68 to 74

The same reaction was performed using the following additives and thesame other reaction conditions as above.

    ______________________________________    Example       additive  yield (%)    ______________________________________    68            PbCl.sub.2                            78    69            PbI.sub.2 75    70            BiCl.sub.3                            72    71            TiCl.sub.4                            74    72            SbCl.sub.3                            68    73            NiCl.sub.2 (bpy)                            71    74            ZrCl.sub.4                            62    ______________________________________

EXAMPLES 75 to 80

The same reaction was performed using the following solvents and thesame other reaction conditions as above.

    ______________________________________    Example       additive    yield (%)    ______________________________________    75            NMP         95    76            DMA         90    77            HMPA        78    78            DMF/CH.sub.3 COOH                              96    79            DMF/CF.sub.3 COOH                              98    80            NMP/CF.sub.3 COOH                              98    ______________________________________

Reference Example 2

Bioorganic and Medicinal Chemistry Letters, 3, 2253(1993) discloses aprocess for preparing a penem compound having β-lactamase inhibitoryactivity, for example, from exo-methylenepenam (5e) obtained by thepresent invention and serving as a starting material. This processgenerally comprises the following steps. An exo-methylenepenam compound(A) is decomposed by ozonolysis into a ketone (B), which is then reactedin the presence of trifluoromethanesulfonyl anhydride and a base toobtain an enoltriflate (C). This compound is reacted with various thiols(RSH) to derive a penem compound (D). The compound is deprotected andpurified, affording a compound (E) having β-lactamase inhibitoryactivity. ##STR14##

(Industrial Applicability)

According to the present invention, a β-lactam halide compoundrepresented by the general formula (2) can be obtained-by a processusing, as a starting material, β-lactam halide compound represented bythe general formula (1) and readily available industrially, in a highyield with a high purity through a safe and simplified procedure, theprocess being developed by realizing milder conditions for effectinghalogenation and a reaction for introducing the leaving group.

Further, an exo-methylenepenam compound of the general formula (5) canbe obtained by a process using, as a starting material, the β-lactamhalide compound of the general formula (2) in a high yield with a highpurity through a safe and simplified procedure by developing a novelmetal reduction system and a novel electroreduction system and therebyeffecting allenization and conversion to an exo-methylenepenam at thesame time efficiently.

We claim:
 1. The process for producing a β-lactam halide compound offormula (2) ##STR15## wherein R¹ is selected from the group consistingof hydrogen, amino and protected amino; R² is selected from the groupconsisting of hydrogen, halogen, C₁₋₄ alkoxy, formyl, acetyl, propionyl,butyryl, isobutyryl and C₁₋₄ alkyl which is substituted by hydroxyl orprotected hydroxyl; R³ is hydrogen or a carboxylic acid protectinggroup; R⁴ is aryl or substituted aryl; X is halogen; n is 0 to 2; and Yis selected from the group consisting of a halogen atom, a substitutedor unsubstituted lower alkylsulfonyloxy group, a substituted orunsubstituted aromatic sulfonyloxy group, a substituted or unsubstitutedhalogenated lower alky sulfonyloxy group, a substituted or unsubstitutedlower alkylphosphoryloxy group and a substituted or unsubstitutedaromatic phosphoryloxy group, the process comprising:reacting a β-lactamhalide compound of formula (1) ##STR16## wherein R¹, R², R³, R⁴, X and nare as defined above, with an agent selected from the group consistingof (a) a halogenating agent, to obtain the compound of formula (2)wherein Y is a halogen atom; (b) a reagent selected from the groupconsisting of (i) a substituted or unsubstituted lower alkylsulfonylchloride, (ii) a substituted or unsubstituted aromatic sulfonic acidchloride, (iii) a substituted or unsubstituted lower alkylsulfonicanhydride, (iv) a substituted or unsubstituted aromatic sulfonicanhydride, (v) a substituted or unsubstituted lower alkylphosphorylchloride and (vi) a substituted or unsubstituted aromatic phosphorylchloride, to obtain the compound of formula (2) wherein Y is selectedfrom the group consisting of a substituted or unsubstituted loweralkylsulfonyloxy group, a substituted or unsubstituted aromaticsulfonyloxy group, a substituted or unsubstituted halogenated loweralkyl sulfonyloxy group, a substituted or unsubstituted loweralkylphosphoryloxy group and a substituted or unsubstituted aromaticphosphoryloxy group; and (c) a reagent selected from the groupconsisting of (i) a substituted or unsubstituted lower alkylsulfonylchloride, (ii) a substituted or unsubstituted aromatic sulfonic acidchloride, (iii) a substituted or unsubstituted lower alkylsulfonicanhydride, (iv) a substituted or unsubstituted aromatic sulfonicanhydride, (v) a substituted or unsubstituted lower alkylphosphorylchloride and (vi) a substituted or unsubstituted aromatic phosphorylchloride, and thereafter reacting the compound with a halogenatingagent, to obtain the compound of formula (2) wherein Y is a halogenatom.
 2. The process of claim 1, wherein the compound of formula (1) isreacted with a halogenating agent, to obtain the compound of formula (2)wherein Y is a halogen atom.
 3. The process of claim 1, wherein thecompound of formula (1) is reacted with a reagent selected from thegroup consisting of (i) a substituted or unsubstituted loweralkylsulfonyl chloride, (ii) a substituted or unsubstituted aromaticsulfonic acid chloride, (iii) a substituted or unsubstituted loweralkylsulfonic anhydride, (iv) a substituted or unsubstituted aromaticsulfonic anhydride, (v) a substituted or unsubstituted loweralkylphosphoryl chloride and (vi) a substituted or unsubstitutedaromatic phosphoryl chloride, to obtain the compound of formula (2)wherein Y is selected from the group consisting of a substituted orunsubstituted lower alkylsulfonyloxy group, a substituted orunsubstituted aromatic sulfonyloxy group, a substituted or unsubstitutedhalogenated lower alkyl sulfonyloxy group, a substituted orunsubstituted lower alkylphosphoryloxy group and a substituted orunsubstituted aromatic phosphoryloxy group.
 4. The process of claim 1,wherein the compound of formula (1) is reacted with a reagent selectedfrom the group consisting of (i) a substituted or unsubstituted loweralkylsulfonyl chloride, (ii) a substituted or unsubstituted aromaticsulfonic acid chloride, (iii) a substituted or unsubstituted loweralkylsulfonic anhydride, (iv) a substituted or unsubstituted aromaticsulfonic anhydride, (v) a substituted or unsubstituted loweralkylphosphoryl chloride and (vi) a substituted or unsubstitutedaromatic phosphoryl chloride, and thereafter reacting the compound witha halogenating agent, to obtain the compound of formula (2) wherein Y isa halogen atom.
 5. The process of claim 1, wherein the halogenatingagent in (a) is selected from the group consisting of a phosphorus(V)chloride, a phosphorus(lll) chloride, a phosphorus(lll) bromide, atriarylphosphine-halogen complex, a thionyl halide, a sulfonyl halideand a mixture of a triarylphosphine or trialkylphosphine and a halogenmolecule.
 6. The process of claim 1, wherein the halogenating agent in(c) is selected from the group consisting of a phosphorus(V) chloride, aphosphorus(lll) chloride, a phosphorus(lll) bromide, atriarylphosphine-halogen complex, a thionyl halide, a sulfonyl halide,an alkali metal halide salt, an alkaline-earth metal halide salt, analuminum halide salt, and a mixture of a triarylphosphine ortrialkylphosphine and a halogen molecule.